Antipsychotic drugs are hypothesized to exert their clinical effects through direct blockade of brain dopamine receptors. Dopamine receptors are characterized in vitro by radioligand binding techniques with dopamine 3H-agonists and 3H-antagonists and by studies of a dopamine sensitive adenylate cyclase. Drug specificities of the cyclase, 3H-agonist and 3H-antagonist binding sites differ from each other, suggesting that each may label different populations of dopamine receptors or different conformations of a single receptor. Only drug affinity for 3H-antagonist binding sites is predictive of antischizophrenic activity. Kainate, 6-hydroxydopamine and surgical lesions demonstrate two distinct populations of dopamine receptors in the striatum: one postsynaptic, cyclase- linked and labeled primarily by 3H-agonists, while the other is located presynaptically on terminals of the cortico-striate pathway, not cyclase-linked and labeled primarily by 3H-antagonists. I propose to investigate (1) the relationship of 3H-agonist and 3H-antagonist binding sites; (2) the pharmacological specificities of pre- and postsynaptic dopamine receptors in isolation; (3) the relationship of dopamine receptor binding sites to the recognition site of the dopamine-sensitive adenylate cyclase; and (4) dopamine receptor regulation by guanyl nucleotides and ions. Decreased dopamine receptor activity caused by denervation or chronic blockade with antipsychotic drugs results in behavioral supersensitivity accompanied by increased dopamine receptor binding. Drug-induced increases in dopamine receptors have been hypothesized to result in tardive dyskinesia. The response of each population of dopamine receptors tc denervation or chronic drug blockade will be investigated to determine the mechanism of the increased receptor binding and any changes in drug specificity or regulatory processes. The effects of chronic stimulation with agonists will also be investigated both in vitro and in vivo. The biochemical characterization of distinct populations of brain dopamine receptors holds promise for the development of new classes of dopamine agonists and antagonists with more specific therapeutic action and lowered incidence of side-effects.